Parkinson’s Disease Worsened by Altered Circadian Rhythm

New research from the Lewis Katz School of Medicine at Temple University (LKSOM) suggests that irregular sleep-wake cycles and chronic insomnia may be risk factors of Parkinson’s disease. In this animal model study, circadian rhythm disturbances before the onset of Parkinson’s disease significantly worsened learning and motor deficits brought on by this disease.

Led by Professor Domenico Praticò, MD from the Center for Translational Medicine and the Department of Pharmacology and Microbiology at LKSOM, this new research is the first to suggest that an environmental factor can exacerbate pathology and symptoms of Parkinson’s. This factor is long periods of chronic exposure to light, with brief exposures to dark, altering the circadian rhythm in the animals. These findings are published in the April version of the journal, Molecular Psychiatry.

The circadian rhythm is a roughly 24-hour biological cycle in humans. This cycle is disrupted in patients with Parkinson’s disease, leading to recurrent sleep disorders and disturbances. However, it is noted that whether these disturbances lead to or impact Parkinson’s disease development and progression is still unclear. Dr. Praticò states that most doctors feel sleep problems are secondary to the disease, but these circadian rhythm disturbances are frequently reported before the onset of symptoms, suggesting that the disturbance is a risk factor.

For the most part, diagnoses of Parkinson’s disease after the age of 60 are idiopathic, or have an unknown cause. Dr. Praticò believes that it is likely in idiopathic cases that the disease comes on as a result of environmental and genetic risk factors. Environmental risk factors can include circadian disturbances, sleep disorders, and chronic stress. All of these factors affect the central nervous system functioning, likely contributing to Parkinson’s pathology.

Using a well-established mouse model of Parkinson’s, where treatment with the neurotoxin, MPTP, reproduces aspects of the disease, researchers analyzed the role of an altered circadian rhythm. The animals were divided into two groups, the first of which was a control group, maintained on a regular sleep-wake cycle and exposed to 12 hours of light and 12 hours of dark every day. The second group was exposed to an altered circadian rhythm, with exposure to 20 hours of light and only four hours of dark every day. After two months (60 days), some of the mice from each group were given MPTP.

Behavior and movement were assessed in all mice treated with MPTP. These mice developed Parkinson’s disease, but the animals that were part of the second group with an altered circadian rhythm had learning impairments. Additionally, they showed extreme motor deficits with huge reductions in motor coordination and learning skills. These deficits were far worse than the deficits seen in MPTP-treated mice that were part of group one.

The researchers analyzed the brains of the affected mice to understand how and why disturbances of circadian rhythm worsened Parkinson’s disease symptoms. One of the major molecular features of Parkinson’s disease is the loss of dopamine production. In this study, Dr. Praticò and his team looked at the region called substantia nigra, in which they saw a significant reduction in the neurons that produce dopamine. Dr. Praticò notes that the epicenter of Parkinson’s disease is the substantia nigra. Normally, cells die naturally here; however, this study showed that an altered circadian rhythm accelerated cell death in this region.

Additionally, microglia (cells) were superactive in the mice that were treated with MPTP and had disruption of their circadian rhythm. This can actually lead to worsening neuroinflammation and speed the progression of the disease.

Going forward, the challenge will be to see if these findings can be replicated in other animal models. If they can be, then researchers will try to re-establish normal circadian rhythm in those who were disrupted to see if that will help reverse brain inflammation and cell death. These study outcomes could have critical implications for the treatment and prevention of Parkinson’s disease in those with chronic sleep disturbances.